tbuckley/cabot-search huggingface dataset:
Post-recurrence survival in asymptomatic compared with symptomatic metastatic breast cancer: A multicenter retrospective study.
Authors: Sayaka Kuba, Shigeto Maeda, Shigeki Minami, Hiroki Moriuchi, Aya Tanaka, Momoko Akashi, Michi Morita, Chika Sakimura, Masayuki Baba, Ryota Otsubo, Megumi Matsumoto, Kosho Yamanouchi, Hiroshi Yano, Kengo Kanetaka, Takeshi Nagayasu, Susumu Eguchi
Journal: Journal of Clinical Oncology (2022)

1049 Background: Asymptomatic metastatic breast cancer (mBC) is often detected using tumor marker or imaging tests in Japan. At the ASCO 2019, we reported on mBC detection, the distribution of symptomatic and asymptomatic disease by subtype (abstract e12568). We aimed to determine whether there are differences in post-recurrence survival (PRS), and treatment between asymptomatic and symptomatic MBCs, and identify factors associated with PRS. Methods: We performed a multicenter, retrospective analysis of patients with mBC treated in our hospitals from 2008 to 2018. Patients were divided into asymptomatic and symptomatic MBCs to compare their prognosis by breast cancer (BC) subtypes: luminal (hormone receptor positive/human epidermal growth factor 2 [HER2] negative), HER2 (any hormone receptor/HER2 positive), and triple-negative (TN) (hormone receptor negative/HER2 negative). Results: Of 204 patients with mBC (114 asymptomatic, 90 symptomatic), PRS was longer in asymptomatic mBC than in symptomatic mBC (median survival: 55 months vs. 29 months; p &lt; 0.001) and tended to have longer overall survival (OS) (110 months vs 72 months, respectively; p = 0.09). In multivariate analysis, TN, recurrence-free survival (RFS), multiple metastasis sites, and symptomatic disease were independently predictive of PRS (Table). In luminal and HER2, PRS trended higher in the asymptomatic group than in the symptomatic group (luminal: 54 months vs. 41 months; p = 0.08, HER2: 71 months vs. 27 months; p = 0.09), but without significant difference in OS (luminal: 112 months vs. 124 months; p = 0.91, HER2: 113 months vs. 72 months; p = 0.40). In the luminal group, 13 patients (11%) were treated with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. The median PRS was 80 months for luminal patients with three factors — longer than 4 years of RFS, a single metastasis site, and asymptomatic disease. The duration of endocrine therapy did not differ between groups; however, the patients with luminal BC in the asymptomatic group had longer chemotherapy than those in the symptomatic group. In TN, PRS was very short (asymptomatic, 28 months; symptomatic, 10.5 months; p = 0.01). Conclusions: We demonstrated that asymptomatic MBC and symptomatic MBC differed in terms of subtypes, prognosis, and duration of chemotherapy in the luminal group. Therefore, unique treatment strategy for asymptomatic or symptomatic MBC should be developed. [Table: see text]
Rethinking the efficacy of awake prone positioning in COVID-19-related acute hypoxaemic respiratory failure – Authors' reply
Authors: Jian Luo, Ivan Pavlov, Elsa Tavernier, John G Laffey, Claude Guerin, David Vines, Yonatan Perez, Oriol Roca, Aileen Kharat, Bairbre McNicholas, Miguel Ibarra-Estrada, Wei Tan, Stephan Ehrmann, Jie Li
Journal: The Lancet Respiratory Medicine (2022)
<i>PTCH1 </i>and <i>AXIN2</i> modulation of AR copy number effects on AR gene overexpression in metastatic castration resistant prostate cancer (mCRPC).
Authors: Raymond T. Yan, Jeanne Latourelle, Omar Khalid, Ravi Bharat Parikh, Bruce W. Church
Journal: Journal of Clinical Oncology (2022)

e17026 Background: Androgen receptor (AR) signaling is a critical pathway in prostate cancer progression. Reactivation of the AR pathway is a key driver in mCRPC. Patients with mCRPC often develop resistance to novel AR signaling inhibitors (ARSIs) such as enzalutamide. AR inhibitor resistance leads to shorter overall and progression-free survival and can be attributed to AR gene amplification with subsequent AR overexpression and androgen-sensitization in prostate tumors. Identifying novel modulators of AR amplification in patients progressing on ARSIs may lead towards potential targets in drug discovery. Methods: In this cross-sectional study, an in silico patient model was developed on prescribed drug therapies and failed therapies patient information, PSA measures, ̃100 mutation variables including somatic, germline, and gain/loss mutations, and ̃1K gene expressions data from 275 mCRPC patients obtained from the Tempus database using GNS Healthcare’s Causal artificial intelligence technology, REFS. A causal network model was reconstructed based on patient data with inferred effect estimates. The network model was topologically surveyed for biological interactions. Results: Causal analysis of this model uncovered two germline mutations, located in PTCH1 and AXIN2, which modify the effect of AR copy number gain ( ARgain+ : copy number 6, ARgain- : copy number &lt; 6) on AR gene expression. For PTCH1-mutant group, there was a 2-fold increase in AR gene expression in ARgain+ patients compared to ARgain- patients (p = 2.1e -12 ), while only 1.4 fold increase in AR gene expression from the PTCH1 non-mutant group (p = 6.3e -08 ). Similarly, there was a 2-fold increase in AR gene expression in ARgain+ patients compared to ARgain- patients (p = 7.2e -16 ) for the AXIN2-mutant group, while only one-fold increase in AR gene expression with the AXIN2 non-mutant group (p = 0.001). The C to T missense mutation in codon 3746 in PTCH1 and codon 148 in AXIN2 have higher prevalences, 55% and 72%, respectively in this mCRPC cohort compared to their population allele frequencies, 38% and 47%, respectively. Conclusions: PTCH1 and AXIN2 mutations from our analyses is consistent with a literature reported role for Hedgehog signaling and Wnt/-catenin signaling pathways, respectively, influencing the disease progression in castration-resistant prostate cancer. Our findings suggest that the missense germline mutations in PTCH1 and AXIN2 predicts response to enzalutamide and other ARSIs in CRPC setting, and propose potential targets for combination therapy to overcome ARSI drug resistance in hormone-refractory prostate cancer. [Table: see text]
Eight-year survival rates by baseline prognostic groups in patients with metastatic hormone-sensitive prostate cancer (mHSPC): An analysis from the ECOG-ACRIN 3805 (CHAARTED) trial.
Authors: Abhishek Tripathi, Yu-Hui Chen, David Frazier Jarrard, Noah M. Hahn, Jorge A. Garcia, Robert Dreicer, Glenn Liu, Maha H. A. Hussain, Daniel H. Shevrin, Matthew M. Cooney, Mario A. Eisenberger, Manish Kohli, Elizabeth R. Plimack, Nicholas J. Vogelzang, Joel Picus, Michael Anthony Carducci, Robert S. DiPaola, Christopher Sweeney
Journal: Journal of Clinical Oncology (2022)

5081 Background: To date there is no prospective survival data beyond 5 years for patients treated with ADT with or without docetaxel (D) when analyzed by well-defined baseline prognostic risk groups and treatment arms. In this updated analysis of the CHAARTED trial, we report the 8-year survival rate based on disease volume and metachronous vs. de novo metastatic disease status with ADT without or with docetaxel. Methods: An updated survival sweep was conducted in February 2022. Patients were prospectively identified by the state of metastatic disease as metachronous (prior local therapy) vs. de novo and low volume (LV) vs. high volume (HV; visceral and/or ≥4 bone metastases with one lesion beyond the vertebral bodies or pelvis) disease. Overall survival (OS) was defined as time from randomization to death or date last known alive and calculated using the Kaplan-Meier method. Results: Of the 790 patients randomized (last patient enrolled December 2012), 238 patients were still alive with a median follow up of 9.7 years for patients still alive. Median OS in the overall population was 60.4 and 47.2 mos in the ADT+ D and ADT arms respectively (Table; HR: 0.77; 95% CI: 0.65, 0.92; p=0.004). ADT+ D was associated with significantly higher 8-yr OS rate (28.5%) compared to ADT arm (15.4%; HR: 0.67; 95% CI: 0.53, 0.84; p=0.0005) in the de novo HV group (n=421). Notably, the 8-yr OS rates were almost doubled for patients with HV disease with early docetaxel (16% vs.30.2%, p&lt;.0001) and this was seen in patients with both de novo and metachronous HV mHSPC. Conclusions: In this long-term updated analysis, ADT+D continued to demonstrate significantly improved OS in the overall population and this is still most clearly evident in patients with de novo HV mHSPC. Our findings highlight the role of baseline prognostic risk groups in predicting longer term survival and benefits from treatment intensification. Clinical trial information: NCT00309985. [Table: see text]
MODL-20. Metabolic rewiring support the onset of chemotherapy resistance in medulloblastoma
Authors: Roberta Bortolozzi, Elena Mariotto, Elena Rampazzo, Lorenzo Manfreda, Chiara Marchioro, Fatlum Rruga, Luca Persano, Giampietro Viola
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma (MB) is the deadliest brain tumor of childhood, intrinsically characterized by fast growth, high invasiveness, and resistance to treatments. With the aim to deepen the molecular basis of MB aggressiveness and recurrence, we established an in vitro model of MB resistance to chemotherapy, in which, a weekly exposure to a cocktail of chemotherapeutics commonly used in MB treatment (Vincristine, Etoposide, Cisplatin, Cyclophosphamide – VECC) induces the selection of cells that progressively acquire resistance to subsequent VECC treatments. Preliminary data on our model of MB resistance show that resistant cells induce the activation of the two main regulator of pentose phosphate pathway TKT and G6PD via the activation of Nrf2 transcriptional activity. Moreover, resistant cells show an increase in hypoxia inducible factor-1α (HIF-1α) together with an augmented expression of glycolytic enzymes HK1, PFKB-3, PDK1 and LDHA and increased glycolytic capacity. Interestingly, enrichment analysis on label free mass spectrometry data reveal that the most significant terms deriving from the upregulated proteins, that characterized resistant cells, were related to metabolic processes such as “carbon metabolism”, “fatty acid beta oxidation”, “tricarboxylic acid cycle” and “carboxylic acid catabolic processes”.Consistently with recent studies that highlight the relevance of metabolic plasticity of cancer cells in chemotherapy adaptation, our data suggest a metabolic uncoupling in which MB resistant cells, through the alteration of peculiar metabolic processes, may satisfy their altered energetic demands through alternative metabolic pathways. In this way, the generation of a new balance of intracellular metabolites finally provide increased resistance to external insults (i.e., chemotherapeutics) and a greater ability of detoxifying the intracellular compartments.
Presentation, management, and outcome of COVID-19 among patients with cancer in the Middle East and North Africa (MENA) region.
Authors: Abdul-Rahman Jazieh, Hikmat Abdel-Razeq, Hakan Akbulut, Adda Bounedjar, Arafat H. Tfayli, Emad M Tashkandi, Wasil A Jastaniah, Jawaher Ansari, Mohamed Osama Alorabi, Amira D Darwish, Ahmed Magdy Rabea, Ashwaq Al Olayan, Fahad Ibnshamsah, Hassan Errihani, Mohammad Alkaiyat, Khaled Alkattan, Fazal Hussain, Suanna Steeby Bruinooge, Elizabeth Garrett-Mayer, Hani Tamim
Journal: Journal of Clinical Oncology (2022)

e18797 Background: Patients with cancer are vulnerable population that suffered during the COVID-19 pandemic from SARS-CoV-2 infection and from the pandemic’s impact on healthcare systems. We are presenting the findings of MENA Registry for COVID-19 and Cancer (MRCC) regarding the SARS-CoV-2 infection presentation, diagnosis, treatment, complications, and outcomes. Methods: MRCC was adapted from ASCO COVID-19 Registry and included patients with SARS-CoV-2 infection and underlying cancer diagnosis including a newly diagnosed cancer in the work-up phase or patients with active cancer receiving cancer therapy or supportive care, or within first year of adjuvant chemotherapy or after one year of curative therapy and receiving hormonal therapy. Registry included data on patients from 12 centers in eight countries in the MENA region, namely: Saudi Arabia, Jordan, Lebanon, Turkey, Egypt, Algeria, United Arab Emirates, and Morocco. The data included patient and disease characteristics, COVID-19 presentation, management, and outcomes. The follow up is differential as data get captured at different points of disease trajectory for each patient which may not reflect the final outcome. Results: Data on 1345 patients were captured in the study by December 7, 2021. Median age was 57.1 years (18-98), whereas 56.1% were females. The median follow-up was 98.5 days (0-554). The most common COVID-19 symptoms was fever (50.3%) and 26.8% of patients were asymptomatic. Out of the 959 patients with complete data on hospitalization, 554 (57.8%) were hospitalized and 126 of them (22.7%) were admitted to intensive care unit (ICU). The majority of hospitalized patients (60%) had respiratory complications and 13.9% had sepsis and 8.5% suffered acute renal injury. As shown in Table, more than quarter of the patients died with 47% of death from COVID-19 or related complication and 60.6% died at home. More than half of the patients were fully recovered from infection. Conclusions: Although more than half of the patients recovered form COVID-19 and more are expected to recover with a longer follow up, the death toll and complications remain high in this patient population. Future analysis of the impact of vaccination and better disease management as well as the impact of newer variants would provide a useful insight on managing this vulnerable population.[Table: see text]
DIPG-01. Targeting p300: A master regulator of childhood diffuse intrinsic pontine glioma (DIPG)
Authors: Pinki Chowdhury, Robert Lober
Journal: Neuro-Oncology (2022)

Abstract Diffuse intrinsic pontine gliomas (DIPG) are heterogeneous, highly aggressive, accounting for ~10% of all childhood central nervous system tumors that are poorly understood. The heterogeneity of the cell populations could contribute to major variability in tumor growth and chemoresistance followed by inadequate treatment responses. Approximately 80% of DIPG patients harbor mutations on lysine-27 of histone-3 (H3K27M), which forms heterotypic nucleosomes with normal, acetylated-H3K27 (H3K27ac), and colocalizes with bromodomain proteins to sites of active transcription. p300 (or EP300) bromodomain has recently been exploited as a potential therapeutic target in other cancer, with a small molecule inhibitor showing antiproliferative activity. Bromodomain inhibitors (BrDi) have been suggested as a potential therapeutic target for DIPG too which showed antiproliferative activity in vitro. We therefore hypothesize that p300 bromodomain inhibition is a potential therapeutic strategy that must be urgently explored in DIPG. p300 is a multi-domain enhancer protein, expressed in 80% of gliomas, responsible for H3K27ac mark and localizes to sites of H3K27ac enrichment, where it serves as an essential binding partner of histones to various transcription factors. p300 interacts with BMI-1, a polycomb repressive complex 1 (PRC1) group of transcription factor, through an intermediate protein NANOG, which promotes cell proliferation in head-neck squamous cell carcinoma. However, immunohistochemical study demonstrated that there is no NANOG expression found in DIPG patient samples. Therefore, we propose that p300 and BMI-1 interact with each other directly or through an intermediate molecule, essential for tumor growth and thus can be considered as a possible therapeutic target for DIPG. The overall outcome of this research will reveal the unexplored mechanisms of DIPG cell proliferation to overcome chemoresistance in sick children and develop drug/combination against this deadly malignancy, which can be used for future clinical trials.
Toripalimab with Fruquintinib as the third-line treatment for refractory advanced metastatic colorectal cancer: Results of a single-arm, single-center, prospective, phase II clinical study.
Authors: Shoucheng Ma, Rui Chen, Xiaoming Hou, Lin Duan, Chunmei Li, Tianning Yang, Xiaoling Ling, Da Zhao
Journal: Journal of Clinical Oncology (2022)

e15573 Background: The most effective treatment of immune checkpoint inhibitors (ICIs) is restricted in microsatellite instability (MSI-H) subsets of advanced colorectal cancer, but MSI-H only accounts for 4-5% among them. Currently, Fruquintinib/ Regorafenib is the standard third-line treatment for metastatic colorectal cancer (mCRC) with microsatellite stable (MSS), which efficacy remains limited in pre-clinical trials. According to the published literature, ICIs has little efficacy in the treatment of refractory advanced mCRC patients with MSS. However, there may be a good synergistic mechanism in the combination of ICIs and anti-VEGFR drugs, which can improve the tumor microenvironment (TME). Our study aimed to evaluate the efficacy and safety of Fruquintinib plus Toripalimab as third-line treatment for refractory advanced mCRC. Methods: This was a single-arm, single-center, phase II clinical trial with 30 patients. Pts received toripalimab (240mg, i.v., Q3W), combined with Fruquintinib (5mg, p.o., 3 weeks on/ 1 week off) until the disease progresses/unacceptable toxicity or receiving the above two drugs as maintenance treatment. The primary endpoint was objective response rate (ORR); the secondary endpoints were disease control rate (DCR), 1-year progression-free survival (PFS) rate, overall survival (OS) and safety. Results: As of Feb 5, 2022, 24 mCRC pts (female: 29.2%, median age: 52.1 years) with ECOG PS ≤ 2 who failed to at least 2 previous lines of therapy containing fluoropyrimidine, oxaliplatin or irinotecan combined with Bevacizumab or Cetuximab were enrolled. The ORR was 16.7% (95% CI：59.7%-94.8%). The DCR was 54.1%, including 4 patients with PR and 9 patients with SD, respectively. 16 patients were alive and the study treatments for 6 patients were still ongoing. Median PFS was 6.0 months (95% CI：3.511-12.489), the 1-year PFS rate was 18%; median OS was 8.0 months (95% CI：1.452-10.548). Overall, 24 pts were enrolled for safety analysis, The most frequent treatment related adverse events were fatigue (50%), hepatocyte dysfunction (36.3%), hypertension (29.1%) and abdominal pain (27.0%). 6 patients (25%) experienced grade 3/4 TRAE (including hypertension, liver enzyme elevation, and immune-associated pneumonia). No treatment-related death was reported. TRAEs leading to either Fruquintinib or Toripalimab discontinuation occurred in 3 (12.5%) pts each. Conclusions: Fruquintinib plus Toripalimab showed certain efficacy and favorable safety profile in refractory advanced mCRC with MSS. It may provide a new choice for mCRC patients who are receiving third-line treatment. The results supported ongoing combined treatment in mCRC patients with MSS and more data will being updated subsequently. Clinical trial information: ChiCTR2000028965.
Increased phosphorylation of RB and protein expression of Cyclin E confers resistance to CDK4/6 inhibitors in dedifferentiated liposarcoma.
Authors: Jocelyn Hsu, Nathan David Seligson, John L. Hays, James Lin Chen
Journal: Journal of Clinical Oncology (2022)

e23525 Background: Dedifferentiated liposarcomas (DDLPS) are malignant adipocytic cancers characterized by an amplification of the cell cycle regulatory gene, CDK4. Palbociclib, a CDK4/6-inhibitor, is a standard of care treatment; however, innate and acquired resistance to the drug limits efficacy in patients with DDLPS. Molecular mechanisms and biomarkers of palbociclib resistance have been posited in non-mesenchymal tumors but are poorly understood in DDLPS. To this end, we developed palbociclib-resistant DDLPS cell lines derived from several DDLPS patient samples to better characterize these phenotypic and genomic differences. Methods: Three human CDK4 amplified DDLPS cell lines (224A, 246, 863) and one control liposarcoma control cell line without CDK4 amplification and RB loss (LiSa2) were brought into culture. Each cell line was intermittently treated with palbociclib at their respective IC 25 for 6 months to develop resistance in long-term treated cell lines. Surviving cells were allowed to recover for at least 2 weeks before retreatment. Parental lines were grown as controls in tandem with the developing resistant lines to compare molecular changes in response to palbociclib. Cell viability was measured by XTT, cell cycle analysis was measured with Flow cytometry using a PI stain, and protein expression was measured using whole cell lysates for Western blotting. Results: The four cell lines had IC50s to palbociclib ranging from 15.0, 14.8, 12.0, and 11.4 µM for LiSa-2, 224A, 246, and 863 cell lines respectively. Long-term treated strains demonstrated consistent reductions in the measured IC50s (8.99, 7.32, 8.27, and 7.08 µM respectively). After treatment with 10 µM of palbociclib for 48 hours, two parental cell lines showed a greater increase in cells in the G1 fraction than long-term treated cells: LiSa-2 (-2.4% increase in parental vs -16.5% increase in long-term treated) and 863 (16.2% vs 11.7%). 224A and 246 demonstrated the opposite where parental cell lines had fewer cells in G1 after treatment compared to long-term treated cell: 224A (12.6% vs. 20.5%) and 246 (12.6% vs. 21.6%). Western blots indicated that the initial response to palbociclib in parental cell lines decreased pRb protein levels and increased Cyclin E and CDK6. After 6 months of treatment for all cell lines, a significant increase in pRb and Cyclin E were observed in the long-term treated cell lines and no changes were seen in CDK4, Cyclin D, nor p16. Conclusions: Here we present the development of two novel, palbociclib resistant, DDLPS cell lines and two long-term treated cell lines. Our resistant cell lines indicated that the ability to bypass the G1/S-checkpoint in the presence of CDK4/6-inhibitors may result from increased phosphorylation of Rb and increased total of Cyclin E. Next generation sequencing of RNA expression in parental and resistant lines are underway.
Relevance of self-masturbation-related vs. coital erectile function in the real-life management of patients with erectile dysfunction
Authors: G. Fallara, E. Pozzi, F. Belladelli, C. Corsini, M. Raffo, L. Candela, A. Costa, D. Cignoli, N. Schifano, A. D'Arma, P. Capogrosso, L. Boeri, W. Cazzaniga, R. Matloob, V. Mirone, F. Dehó, F. Montorsi, A. Salonia
Journal: European Urology (2022)